The effects on food intake of repeated administration of d-amphetamine and fenfluramine were examined in rats adapted to a 4 hr/day feeding schedule. Control rats given daily injections of amphetamine before food access rapidly developed a partial tolerance to the food intake reducing effect of amphetamine. However, rats given a 6-hydroxydopamine (6-HDA) treatment which produced a large selective depletion of dopamine in brain failed to display tolerance to amphetamine-induced anorexia after either 10 or 23 days of amphetamine injections. Although higher than normal doses of amphetamine were required to reduce feeding in 6-HDA-treated rats, control rats displayed tolerance after repeated injections of drug doses which were either equianorexic or equivalent to doses used in rats given 6-HDA. Furthermore, 6-HDA-treated rats failed to display tolerance to the low amphetamine doses normally used in control rats. In contrast to the results with amphetamine, both control and 6-HDA-treated rats displayed tolerance to the anorexic effect of fenfluramine. These results suggest that central dopaminergic neurons are involved in the tolerance which normally develops to the anorexic effect of amphetamine.